Hundreds of different viruses are able to infect humans. The biology, life cycle and pathogenesis of different viruses are widely divergent. Nevertheless, based on current knowledge, it seems that the immune system employs mainly the same mechanism of antiviral protection to battle any type of virus. This mechanism relies on the action of type I interferons, IFNalpha/beta. These secreted proteins are released by virus-infected cells to warn neighboring cells about viral presence and to force the cells to deploy various means of antiviral protection. The robust production and secretion of type I IFNs in response to viral infection is currently considered to be a key event in the establishment of a multi-faceted antiviral response. However, recent discovery of a novel ligand-receptor system that, upon engagement, leads to the establishment of an antiviral state by a mechanism similar to, but independent from type I IFNs, opened a new direction in antiviral research. Three highly homologous proteins, distinct from type I IFNs, are capable of inducing antiviral protection. The proteins were designated IFN-lambdas (IFN-lambda1, IFN-lambda2 and IFN-lambda3), based on their antiviral activity. IFN-lambdas are also capable of up-regulating MHC class I antigen expression. Consistent with their role in antiviral response, the expression of IFN-lambda mRNA is inducible in several cell lines in response to various viruses. The IFN-lambda receptor complex have been identified and found to be distinct from the type I IFN receptor complex. Although IFN-lambda does not use the IFN-alpha/beta receptor complex for signaling, both IFN-lambda and IFN-alpha/beta induce overlapping biological activities and signaling events. Many questions related to the discovery of IFN-lambda antiviral system are still to be answered by future experiments, and are the focus of the current grant. The proposed project is designed to further investigate the biological activities of IFN-lambdas, to correlate their actions with those of type I IFNs, and to determine relationship between the IFN-lambda and type I IFN antiviral systems. Specific aims of the project are: to investigate expression of IFN-( genes in dendritic cells (DC) and activities of IFN-lambdas on DC and monocytes; to characterize differences in signal transduction events and protein expression profiles in response to IFN-lambda and IFN-alpha/beta using proteomics, and correlate them with biological activities; to study transcriptional regulation of IFN-lambda genes; and to create mice with disrupted IFN-lambdaR1 gene and study their phenotype.